P665: CARDIAC ADVERSE EVENTS AND SECOND PRIMARY MALIGNANCIES WITH ACALABRUTINIB IN CHRONIC LYMPHOCYTIC LEUKEMIA -A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Authors: K. Parmar, D. Pawar, K. Bharathidasan, G. DelRioPertuz, L. Tijani
Journal: HemaSphere (2022)

Background: Cardiac adverse events were the most common cause of treatment discontinuation in patients with chronic lymphocytic leukemia (CLL) on ibrutinib. Acalabrutinib is a new, selective, irreversible Bruton’s tyrosine kinase inhibitor (BTKi) that is approved for the treatment of CLL. Patients with CLL are inherently immunodeficient and are at increased risk of second primary malignancies (SPM). Additionally, BTKi have been studied in association with risk for secondary malignancies. The risk of cardiac adverse events and SPM with acalabrutinib in patients with CLL. Aims: We conducted this systematic review and meta-analysis to estimate risk of cardiac adverse events and SPM with acalabrutinib in patients with CLL. Methods: A comprehensive literature search was performed in PubMed, EMBASE, Clinical trials.gov and meeting abstracts till January 31,2021. All randomized controlled trials comparing acalabrutinib-based regimens with a control group in patients with CLL, with cardiac adverse events and SPM reported as adverse effects were included. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method of the fixed-effect model. Heterogeneity of effect size was quantified using the I2 statistic. Statistical analysis was performed using the Review Manager, version 5.3. Results: Three phase III RCT with total of 1362 patients were included for our analysis (Figure). Byrd et al., compared acalabrutinib with ibrutinib. The ASCEND trial compared acalabrutinib with investigator’s choice chemotherapy, either idelalisib plus rituximab or bendamustine plus rituximab. In the ELEVATE -TN study, the comparator arm included the combination of chlorambucil and Obinutuzumab. Acalabrutinib was used at a dose of 100 mg twice daily in all 3 studies. All but ELEVATE -TN study included patients previously treated with CLL. Atrial fibrillation was the most common cardiac adverse event across all trials. Non melanoma skin cancer was the most common SPM across all trials. There was no increase in any grade cardiac adverse events with acalabrutinib when compared to control arm (pooled RR 1.06; 95%CI 0.84-1.34). There was no increased risk of atrial fibrillation (pooled RR 0.85; 95%CI 0.57-1.26), ventricular arrythmias and cardiac arrest (Figure). There was significant increase in hypertension (HTN) in the patients on the acalabrutinib containing regimens (pooled RR 1.78; 95%CI 1.24-2.56; P= 0.002); however, there was no increase in grade 3+ HTN. There was a decrease in the SPM with acalabrutinib as compared to the control group (pooled RR 0.67; 95%CI 0.46-0.96; P= 0.03) (Figure). There was also significant decrease in non-melanoma skin cancer in the acalabrutinib as compared to the control group (pooled RR 0.59; 95%CI 0.37-0.93; P 0.02). There was no significant difference in the genitourinary cancer, lung cancer and hematologic cancer. Image:Summary/Conclusion: There is no increase in risk of atrial fibrillation with the acalabrutinib based regimens as compared to the non-acalabrutinib – based therapies; however, there was a significantly increased risk of HTN. There is lower risk of SPM and non-melanoma SPM in the acalabrutinib based regimens than the control arm.